The present invention relates to a process for the preparation of difluorobenzenes.
Fluorobenzene is produced by processes such as diazotization of aniline using NaNO.sub.2 in HF followed by decomposition as taught by Chem. Abs. 104, 109476b (1986); gas phase reaction of fluorine and benzene as taught by Chem. Abs. 76, 112801n (1972); and pyrolysis of mixtures of dienes and fluorochloromethanes as taught by Chem. Abs. 71, 80903a (1969).
The main process for production of meta- or of arene diazonium tetrafluoroborates as taught by Balz et 1,3-difluorobenzene is based on the thermal decomposition al, Ber. 60, 1186 (1927). The first step of the process involves the preparation and isolation of a dry diazonium fluoroborate while the second step deals with the controlled decomposition of the salt by heat to yield an aromatic fluoride, nitogen, and boron trifluoride. According to Schiemann et al., Ber. 62, 3035 (1929), 1,3-difluorobenzene was prepared in 31% yield from the bis-diazonium salt derived from m-phenylenediamine. See also Roe, Organic Reactions 5, 193(1949) and Suschitzky, Advances in Fluorine Chemistry 4, 1(1965) for detailed analyses of the Balz-Schiemann Reaction.
In attempts to improve yields and facilitate product recovery, modifications of the Balz-Schiemann reaction as applied to the synthesis of 1,3-difluorobenzene have appeared over the years. Chem. Abs. 54, 5518c (1960) discloses the thermal decomposition of various haloaniline fluoroborate salts to fluorobenzenes. The process requires multiple steps including the preparation of the haloanilines and their subsequent diazotization, isolation, and decomposition. Based on the last step, 1,3-difluorobenzene was prepared in a 57% yield.
Chem. Abs. 56, 3408 g (1962) teaches the diazotization of meta-phenylenediamine in sulfuric/glacial acetic acid and subsequent treatment with HBF.sub.4. The dried diazonium salt was decomposed thermally in small portions at 210.degree. C. to yield 45% 1,3-difluorobenzene.
According to Hartman et al., "Crown Ether-Copper-Catalyzed Decomposition of Arenediazonium Fluoroborates," J. Org. Chem. 42(8), 1468 (1977), 2,4-difluorobenzenediazonium tetrafluoroborate was decomposed in methylene chloride under a nitrogen atmosphere in the presence of catalytic amounts (10 mol %) of dicyclohexyl-18-crown-6(1) and powdered copper for 15 minutes at 40.degree. C. to yield 1,3-difluorobenzene in 95% yield. The Hartman et al. process is disadvantageous because the process requires isolation of the diazonium salt, uses toxic and expensive crown ethers which have to be recovered or recycled, and uses starting materials which are not commercially available. The reported yields are not isolated but are based on GC analysis.
U.S. Pat. No. 4,075,252 discloses a process wherein a suitable amine substrate is diazotized with a diazotization agent in hydrogen fluoride to form the corresponding diazonium fluoride. This diazonium fluoride is thermally decomposed to form the aryl fluoride. The Examples teach that using 3-fluoroaniline as a starting material, the yields for 1,3-difluorobenzene were on the order of 46% for the two-step process. This approach is economically unattractive as an industrial process because 3-fluoroaniline is unavailable in commercial quantities.
U.S. Pat. No. 4,096,196 is an improvement on U.S. Pat. No. 4,075,252 in that the diazotization/fluorination is conducted in a hydrogen fluoride medium containing tertiary amine compounds. The Examples teach that using 3-fluoroaniline as a starting material, the yields for 1,3-difluorobenzene were on the order of 70%. Again, such an approach is economically unattractive as an industrial process because 3-fluoroaniline is unavailable in commercial quantities.
In the Balz-Schiemann Reaction, isolation and controlled decomposition of diazonium fluoroborates or diazonium fluorides are troublesome synthetic procedures, particularly on a large scale and repeated nitrations and reductions are necessary to substitute more than one fluorine on the aromatic substrate. The process is also complicated by side reactions which occur during the diazotization or the decomposition stage and which result in the formation of tars, unexpected replacement of the diazonium group by hydrogen, or unwanted displacement of fluorine by ancillary halides usually present as a contaminant in the diazonium salt. These occurrences result in decreased yields of 1,3-difluorobenzene and purification difficulties.
Alternative processes to the Balz-Schiemann reaction have been investigated but with little success. Gunther et al, Ber. 98 3410 (1965) teach the continuous gas phase fluorination of benzene or fluorobenzene with chlorine trifluoride/nitrogen gas mixtures; yields of 1,3-difluorobenzene were on the order of 4%. Other processes include heating mixtures of butadiene and CHF.sub.2 Cl at 650.degree. which produced a mixture of 48% ortho-, meta-, and para-difluorobenzenes according to UK Pat. No. 1,130,263; reacting trichlorobenzenes with potassium fluoride or potassium fluoride-cesium fluoride mixtures in dimethylsuflone which produced 1,3-difluorobenzene as a by-product in low yields of about 2 to 4% according to Shiley et al, "Fluorination of 1,2,3-; 1,2,4-; and 1,3,5-Trihalobenzenes with Potassium Fluoride in Dimethyl Sulfone," J. Fluorine Chem. 2, 19 (1972); reacting atomic fluorine with bromobenzene vapor which produced 1,3-difluorobenzene as a by-produce in low yields according to Vasek et al, "Radio frequency Fluorination of Bromobenzene using Elemental Fluorine," J. Fluorine Chem. 2, 257 (1972); and reacting atomic fluorine with fluorobenzene under cold plasma which produced 1,3-difluorobenzene in low yields according to Vasek et al, "The Reaction of Atomic Fluorine with Fluorobenzene," J. Fluorine Chem. 3, 397 (1973).
According to Sams et al, "Molecular Sieve Fluorination of Fluorobenzene Using Elemental Fluorine," J. Org. Chem. 43(11), 2273 (1978), attempts were made to prepare 1,3-difluorobenzene using a molecular sieve fluorination technique. Fluorination of monofluorobenzene resulted in the isolation of various isomers of difluorobenzene in 19% yield; the highest reported yield for the meta isomer was 1.2%.
Difluorobenzenes are employed as chemical intermediates in a variety of applications including pharmaceutical and agricultural. For example, 1,3-difluorobenzene is used in the preparation of Diflunisal (trademark), an anti-inflammatory agent, or in Diflubenzuron (trademark), a potential insecticide. Benzodiazepinones are prepared by reacting 1,2- or 1,4-difluorobenzene in a multistep procedure to yield compounds which exhibit sedative and/or anticonvulsant activity; see U.S. Pat. Nos. 3,816,409 and 4,031,221. Fluorobenzene may also be polymerized to produce products which exhibit good thermal resistance or electrical insulation properties and may also be deposited on other types of polymers to modify their surface characteristics as in U.S. Pat. No. 3,386,899. Because difluorobenzenes are so commercially useful, a simple process for the preparation of difluorobenzenes in good yields is needed.